Professor Dr Lorenz C Hofbauer, MD leads the Division of Endocrinology, Diabetes and Bone Diseases at the Technische Universität Dresden Medical Center. Here, he describes his laboratory and explains how he sees research in this area progressing
The State of Saxony has made a unique effort to create a place of scientific excellence at the University of Dresden. A central component of this scientific excellence has been created in the field of medicine and biomedical research, especially in the research and treatment of diabetes. Following an international complex review process the “Technische Universität Dresden” (TU Dresden) has been chosen as one of the 11 German elite universities. Diabetes research is a major focus in the clusters of excellence at the TU Dresden that led to this success.
Diabetes - current and future visions
Currently, more than 300 million people worldwide suffer from diabetes and the number of patients is increasing dramatically. The disease is characterized by increased blood glucose concentrations and on the long run diabetes may result in severe damage to blood vessels, nerves, heart, kidney and other organs. Dresden has a long standing tradition in the field of diabetes: Shortly after discovery of insulin, Dresden installed the first diabetes clinic in Germany in 1922. Many years later, in 1981, the concept of the metabolic syndrome was also coined in Dresden. Nowadays, Dresden has become one of the largest diabetes centers in Europe.
Professor Stefan R. Bornstein, Director and Chair of the Department of Internal Medicine at the University Hospital Carl Gustav Carus Dresden: “Our center offers several unique features to patients including an islet transplantation program and the first European Department for the prevention of diabetes. The latter, for example, offers the enrollment into special programs in order to detect specific risks and – based on this - develop individual strategies to prevent the disease. Furthermore, the hospital has one of the largest insulin pump outpatient clinics with more than 400 patients.” At large 30,000 patients benefit every year from the experienced specialists at the University Hospital Carl Gustav Carus Dresden.
Individual treatment in accordance to the latest research
How is diabetes related to stress and depression?
Comparable to diabetes mellitus, other lifestyle-related conditions like stress and stress-related diseases are on the rise. For example, we currently observe a dramatic increase in depression which is one of the most stressful conditions for human beings. This is well documented and reflected by the fact that the levels of cortisol – a major stress hormone - are usually elevated in patients suffering from depression. Cortisol is a major hormone produced by the adrenal gland that is essentially required to adapt the organism’s metabolism in response to stressful stimuli. This results in a rapid mobilization of energy resources that are required to cope with the challenge. However, permanent overproduction of cortisol may also result in negative consequences like loss of muscle mass and impairments of glucose metabolism ranging from increased blood glucose concentrations to diabetes mellitus. Furthermore, antidepressant therapy is frequently associated with metabolic aberrations that are mainly due to the commonly observed weight increase of patients treated with antidepressants. Taken together, the hormonal and metabolic changes associated with stress, depression and diabetes have a great deal in common and share an interesting background.
How is diabetes related to nutrition and the microbiome
The microbial colonization of the gut may play a critical role in human health and disease and the number and composition of gut microbes varies between individuals. The human gut microbiome consists of more than 1.000 different germ species and the sum of the gut microbial genomes, the so-called metagenome, exceeds by far the size of the human genome. Novel, cutting-edge sequencing technology (so-called “Next-Generation Sequencing”) has made it possible to characterize the human metagenome and recent studies performed with fecal DNA of individuals from Europe, Asia and the US have suggested an association between specific metagenomic constellations and the risk for obesity and type-2-diabetes, most likely due to differences in microbial energy metabolism.
Based on this background, the current focus of one research project conducted at Dresden diabetes center is on the metagenome of morbid obese patients with type-2 diabetes who underwent gastric bypass surgery. Interestingly, shortly after operation a dramatic improvement of glucose metabolism can be usually observed in these patients, even before weight loss.
In a pilot study, the Dresden group analysed the intestinal metagenome of patients before and 3 months after gastric bypass surgery. Interestingly, it turned out that the metagenome in all observed patients rapidly changed from a pattern associated with a high risk for diabetes into an pattern with a lower risk. This study thereby provided the first evidence for an essential role of the gut microbiome in the anti-diabetic effects of gastric bypass surgery.
In the near future further exciting and important insights can be expected from this new field of research and we are now only at the beginning to understand the comprehensive role of the gut flora in human health and disease. The long term goal of Professor Bornstein and his team is to develop metagenome-based approaches for the development of novel strategies for the prevention and treatment of diabetes.
Has diabetes a genetic background?
Diabetes is a multifactorial disease and in particular the recent genom-wide association studies (GWAS) have revealed a more or less strong association of several genes with the risk to develop type-2-diabetes. For example, TCF7L2 has been identified as a gene with the strongest risk associated with the development of type-2-diabetes. However, things are much more complex due to the fact that a variety of other, mostly still unknown factors are essentially involved in the regulation of gene expression. These – so-called epigenetic - factors may be of environmental or microbial origin and are thought to be the true risk determinants responsible for the interplay of different genes resulting in an individual’s risk constellation.
How can we cure diabetes? – shift in paradigm
For the majority of patients with type-1-diabetes, the treatment with insulin is a very reliable and safe therapy and helps to reduce or prevent diabetes-associated complications. Intensive insulin therapy with several daily injections or with an insulin infusion pump has been shown for many years to be an effective method of maintaining blood glucose concentrations in an acceptable range. However, despite optimal medical therapy, a rare number of patients suffering from insulin-dependent diabetes show a poor control of the disease and experience repeated and unpredictable lapses of blood glucose levels to both ends of the spectrum ranging from severe hypo- to uncontrolled hyperglycemia resulting in severe and potentially life-threatening conditions.
Whole organ pancreas and pancreatic islet transplantation are currently the only options available to replace the insulin-producing ß-cells in patients. Both therapeutic options can provide good control of diabetes and a prevention or stabilization of diabetic complications. The insulin producing cells are isolated from the pancreas (donor organ), purified, and then injected into the blood vessels of the liver of the diabetic patient (recipient) through a small abdominal incision. The pancreatic islet cells engraft in the liver and start to produce the recipient with insulin.
In 2008, the Dresden Diabetes Center successfully launched an islet cell transplant program for the treatment of type-1-diabetes. Professor Bornstein: “Islet transplantation has been developed as a treatment for type-1-diabetes mellitus in selected patients with inadequate glucose control despite optimal insulin therapy. The primary goal of this therapeutic option represents enhanced metabolic control, prevention of severe complications and significant improvement of quality of life.”
However, cell and organ transplantation is generally at the price of permanent immunosuppression, thereby making the patient prone to infections and other potentially severe side effects. Therefore, this therapy is restricted only to a small subset of diabetic patients that need to fulfill a number of specific criteria.
In this situation, novel therapeutic options are urgently needed. A new, visionary development could soon become reality: the Dresden scientists currently explore a small capsule harbouring insulin producing cells that was originally developed in Israel. This bioreactor is designed as an implantable device working as an artificial islet organ in order to supply diabetic patients with insulin. The unique advantage of this novel technique is that it effectively separates the donor cells from the recipient’s immune system, thereby making the traditional immunosuppressive therapy completely dispensable.
How can we prevent diabetes?
Type-2-diabetes is the most common metabolic disorder in the world. Currently, with more than 6 % of the world’s adult population we are experiencing an epidemic growth of the number of patients suffering from type-2-diabetes. This development goes hand in hand with the ‘westernization’ of our lifestyle, meaning the increasing consume of more energy-dense food as well as decreasing physical activity. Driven by this development, type-2-diabetes in particular affects more and more young people during their working life. The medical burden is expressed by the growing number of patients with diabetes-related complications also resulting in an enormous economic burden. The latter is expected to also severely impair global economic growth in the near future. The number of worldwide citizens affected by chronic diseases defines the necessity to develop better management and care programs including early detection and treatment strategies as well as investments into the development and implementation of prevention programs. The Dresden diabetes center introduced the first professorship for research on prevention and care of diabetes in Europe and offers specialized and customized programs aimed at an early detection and potential prevention of the disease. The Dresden diabetes competence center also developed the first European guideline for diabetes prevention and training programs to educate certified prevention managers. This concept is today used in more than 20 countries in the European Union and also introduced into practical diabetes care.
Close research associations, for example:
Paul Langerhans Institute Dresden
The foundation of the Paul Langerhans Institute Dresden (PLID) as one of the five selected partners of the DZD (German Center for Diabetes Research) is based on the Dresden “excellence in diabetes research”. The PLID maintains a close relationship with the Department of Internal Medicine, thereby ensuring a direct transfer of lab research results into clinical applications (“from bench to bedside”). Based on a strong interdisciplinary expertise in genetics, cell and developmental biology, the focus of the PLID is in the field of regenerative medicine. For example, currently scientists of the PLID are working on concepts to prevent the destruction of insulin producing beta cells and to restore beta cell function and regeneration. Further, the PLID is integrated into a scientific network with other national and international programs including Clinical trials.
CRTD/ DFG Research Center for Regenerative Therapies Dresden – Cluster of Excellence at the TU Dresden
Recognition of Dresden's scientific and clinical strengths in the area of regenerative medicine is evidenced by the funding of the CRTD as a Deutsche Forschungsgemeinschaft Excellence Cluster. Established in 2006, it has been instrumental in attracting leading international scientists in the area of regenerative biology and Medicine, including diabetes, to Dresden. The CRTD takes advantage of model organisms that have very efficient regenerative capacities in order to understand how the process can be reinstated in man. Diabetes is one of the four target diseases of the CRTD. The Diabetes research program within the CRTD intensively studies ways in which the insulin-producing beta cell can be regenerated and protected so that new therapies to prevent and cure diabetes can be developed. One of these is a unique program of type 1 diabetes prevention. Professor Bonifacio from the CRTD leads an international clinical study in which infants who have a strong genetic predisposition to develop type 1 diabetes are immunised in an attempt to prevent the disease process from starting. It is hoped that this clinical trial will provide a major break-through in one of our more common chronic diseases of childhood and thereby reverse the increasing incidence of type 1 diabetes.
Professor Bornstein: “We follow the vision to promote cutting-edge developments in Dresden that are unique in the world. We look for new and more powerful ways to treat and prevent diabetes in order to better help more people in the future”.